The invention relates to high purity (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane and pharmaceutically acceptable acid addition salts thereof and a process for the preparation of these compounds as well as medicaments containing 1 or more of these compounds and their use.
The 2-(E)-butenedioate (1:1) salt (fumarate) of (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo([2.2.1]heptane of Formula 
is a known anxiolytic active principle having the INN xe2x80x9cderamciclane fumaratexe2x80x9d.
The compound of Formula I falls under the general Formula I of Hungarian patent No. 179,164 but has not been actually and explicitly disclosed in this patent specification, nor the preparation thereof has been exemplified. According to Hungarian patent No. 179,164 the alkanol amine cycloalkyl ethers of its general Formula I are prepared by reacting (+)-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one, i.e. (+)-camphor of Formula 
with the corresponding organic metal compound, subjecting the adduct obtained to hydrolysis and introducing onto the hydroxy group of the product obtained the basic side chain by etherification. As organic metal compound a Grignard compound or an organic alkali metal compound, preferably lithium or sodium compound, is used.
The preparation of the compound of Formula I has been actually disclosed in Hungarian patent No. 212,574. The essence of this process is that purification of the product is carried out at a later stage of the synthesis. According to the process (+)-camphor of Formula II is subjected to Grignard reaction with phenyl magnesium bromide in diethyl ether to give (1R,2S,4R)-(xe2x88x92)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formula 
with a yield of 28% (according to GC). The compound (1R,2S,4R)-(xe2x88x92)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formula II is in the reaction mixture and is not isolated. The complex is decomposed, the reaction mixture is converted without purification into the sodium salt by reaction with sodium amide or sodium hydride and the sodium salt obtained is reacted with anhydrous (2-{chloro}-ethyl)-dimethylamine in toluene as medium. The reaction mixture contains beside the base (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I (being present in an amount of 20 to 30%) a considerable amount of impurities and starting materials, e.g., unreacted (+)-camphor of Formula II, (1R,2S,4R)-(xe2x88x92)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol, 1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol and biphenyl, triphenyl impurities, etc. The base (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I is separated from said contaminations by extraction with aqueous tartaric acid, whereupon the base is set free and the fumarate salt is formed. The total amount of unreacted (+)-camphor of Formula II and (1R,2S,4R)-(xe2x88x92)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formula III remains in the organic phase of the tartaric acid extraction step, which can be re-used in the Grignard reaction after removing the solvent and water (i.e. it can be re-circulated into the process). Thus the (+)-camphor used can be more efficiently utilized; without re-circulation only about 16% by weight of the (+)-camphor used can be utilized, while in case of a one-fold and three-fold re-circulation this value is increased to 22% by weight and 25% by weight, respectively.
It is very important and is to be emphasized that a considerable part of (+)-camphor of Formula II used in the Grignard reaction does not react and this starting material cannot be technically removed from the desired product because of physical properties of (+)-camphor and the lability of the compound (1R,2S,4R)-(xe2x88x92)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formula III formed since compound (1R,2S,4R)-(xe2x88x92)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formula III susceptible to decomposition. For this reason according to the process disclosed in Hungarian patent No. 212,574 the alkylation step always takes place in the presence of (+)-camphor of Formula II.
The aforesaid gives rise to the drawbacks of the process disclosed in Hungarian patent No. 212,574. The alkali hydrides and amides used in the first step of the alkylation reaction form salts not only with the alcohol (1R,2S,4R)-(xe2x88x92)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formula III but also with (+)-camphor of Formula II and other compounds containing an active hydrogen atom being present in the reaction mixture. For this reason beside the desired compound (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I further alkylated derivatives formed, e.g. from unreacted (+)-camphor, are obtained and the desired compound (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I is to be recovered from a mixture containing such impurities and also unreacted compounds (+)-camphor and (1R,2S,4R)-(xe2x88x92)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formulae II and III. The crude compound (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I can only be purified, though incompletely, by means of recrystallization from dimethyl formamide. However, with the aid of said recrystallization only non-basic contaminations can be completely removed, which do not form salts.
A further disadvantage of recrystallization from dimethyl formamide is that the traces of the solvent cannot be removed from the desired pharmaceutical active principle to the required extent. In this regard it is to be noted that according to ICH (International analytical requirements accepted by the US, Japan and the EU) the limit of dimethyl formamide is 880 ppm (0.088% by weight). The reason for that the dimethyl formamide cannot be removed to such an extent but a greater amount of it remains in the product is the high boiling point of dimethyl formamide, on the one hand, and the sensitivity of (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I to thermal treatment, on the other hand.
It has been found that in case of the alkylation reaction of (1R,2S,4R)-( )-)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formula III carried out with (2-{chloro}-ethyl)-dimethylamine (+)-camphor of Formula II being always present gives rise to the formation of considerable amounts of by-products, e.g. (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one of Formula 
The by-product (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one of Formula V is formed as follows: under the conditions used in the etherification reaction (+)-camphor of Formula II forms an alkali salt in position 3 which in turn reacts with the (2-{chloro}-ethyl)-dimethylamine used as alkylating agent to yield the compound of Formula V. The amount of the by-product of Formula V may be as high as 1 to 10%. The solubility of the fumarate 2-(E)-butenedioate (1:1) of the compound of (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one of Formula V is approximately identical with that of the fumarate of the desired compound (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I and therefore crystallizes together with the fumarate of the compound (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I and contaminates the desired end product. If the etherification is carried out in toluene, as described in Hungarian patent No. 212,574, the product obtained after salt formation in ethanol contains considerable amounts of the impurity (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one of Formula V.
The salt is a highly unsoluble compound and can be recrystallized only from dimethyl formamide. However, recrystallization from dimethyl formamide fails to provide a compound (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I in a purity required by the Pharmacopoeias for the following reasons:
a) The product obtained after recrystallization from dimethyl formamide still contains the compound (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one of Formula V in an amount above the threshold value permitted by Pharmacopoeia (about 0.5%);
b) Dimethyl formamide has a high boiling point and cannot be removed from the product in the required degree because at the high temperature decomposition of the product takes place.
A purification to yield products with a purity sufficient for medicaments according to the Pharmacopoeias could not be attained by known purification processes, such as recrystallization from solvents or fractional distillation. More specifically, by known processes the (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I could not be obtained having no more than 0.2 of (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one Formula V but only with more than 0.5% of this impurity.
Taking into consideration the severe requirements of Pharmacopoeia, impurities being present in an amount higher than 0.2% by weight may endanger the use of the active principle for pharmaceutical purposes. The impurity (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one of Formula V may therefore cause problems in the use of the compound of Formula I as active principle.
As a summary, it can be stated that when purifying the (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I prepared by the known method, dimethyl formamide would be the only conceivable solvent. However, this recrystallization method is unsuitable for the preparation of a pharmaceutical active ingredient meeting the requirements of the Pharmacopoeias, because dimethyl formamide has such a high boiling point that traces thereof cannot be removed from the product to a sufficient extent. At the high temperature required the compound (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I is subject to decomposition.
As already disclosed above, (+)-camphor of Formula II is present during the alkylation reaction. From (+)-camphor as further contamination (1R,4R)-2-[(2xe2x80x2-{N,N-dimethylamino}ethoxy)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula 
is formed. If an alkali metal hydride or alkali metal amide is used as basic salt forming agent, the amount of the contamination (1R,4R)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula IV is 1 to 10%. The compound (1R,4R)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula IV has been known from the Prior Art [Yakugaku Zasshi, 75, 1377, (1955); Chem. Abstr. 9340 (1956)]. The compound (1R,4R)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula IV is formed as follows: the alkali metal hydride or alkali metal amide used for sodium salt formation in the etherification step reduces 1 to 10% of (+)-camphor of Formula II to borneol which is converted under the reaction conditions used into the alkali metal salt and said alkali salt enters with (2-{chloro}-ethyl)-dimethylamine into an alkylation reaction. However, the borneol ether (1R,4R)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula IV can be separated from the desired compound (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-[N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I in the course of working up the reaction mixture.
The problem underlying to the invention is to provide (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I and pharmaceutically acceptable acid addition salts thereof containing amounts of (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one of Formula V small enough to meet the requirements of use for pharmaceutical purposes and a process for preparing such compounds without the necessity of recrystallization purification steps which anyhow would lead only to an insufficient purification and would reduce the yield and moreover would have the drawback that the residual solvent could not be removed from the end product to a sufficient extent even by complicated methods, as well as medicaments containing 1 or more of these compounds and their use.
Surprisingly the above has been solved by the present invention which provides a new product that could not be prepared by the Prior Art.
The present invention is based on the surprising recognition that if the reaction between the reaction mixture containing the compound (1R,2S,4R)-(xe2x88x92)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formula III and (2-{chloro}-ethyl)-dimethylamine is carried out in the presence of an alkali metal hydride or alkali metal amide in a medium containing dioxane as solvent, the reaction is directed by far in favour of the formation of the desired (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I and the by-product (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one of Formula V is formed only in a minimal amount. The above recognition enables the preparation of the desired compound (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino)-ethoxy)]-2-[phenyl-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I containing less than 0.2% of compound (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one of Formula V. The compound (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I thus obtained directly meets the requirements of Pharmacopoeia as regards the purity and the content of residual solvent.
In the entire text the percentages regarding the contents of the compounds of Formulae I and V and of other compounds are the result of gas chromatographic analysis they being the ratio of the area under the given peak and the total area under all the peaks.
Hence a subject matter of the invention are (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula 
and pharmaceutically acceptable acid addition salts thereof, characterised by that they contain not more than 0.2% of (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one of Formula 
or of a pharmaceutically acceptable acid addition salt thereof.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d used in the present patent specification means salts formed with inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or organic acids, e.g. acetic acid, tartaric acid, succinic acid, malic acid, lactic acid, citric acid, maleic acid or fumaric acid. The salt formed with fumaric acid possesses particularly useful properties.
The (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I has three asymmetrical centers, namely in positions 1, 2, and 4.
According to a preferred embodiment of the invention there is provided for (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane fumarate (1:1), characterised by that it contains not more than 0.2% of (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one fumarate (1:1).
Particularly preferably the above (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I and pharmaceutically acceptable acid addition salts thereof according to the invention are characterised by that they contain not more than 0.1%, particularly not more than 0.05%, of the (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one of Formula V or of a pharmaceutically acceptable acid addition salt thereof.
Furthermore particularly preferably the above (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane fumarate (1:1) is characterised by that it contains not more than 0.1%, particularly not more than 0.05%, of the (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo2.2.1]heptane-2-one-fumarate (1:1).
Another subject matter of the invention is a process for preparing the (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I and pharmaceutically acceptable acid addition salts thereof according to the invention by converting (+)-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one {(+)-camphor} of Formula 
into (1R,2S,4R)-(xe2x88x92)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formula 
by reacting the former with a metallo-organic compound, if necessary carrying out a decomposition, conveniently hydrolysis, of the reaction product, and reacting the (1R,2S,4R)-(xe2x88x92)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formula II thus obtained with a (2-{halogeno}-ethyl)-dimethylamine in the presence of a basic salt forming agent in an organic solvent and, if desired, converting the base (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I thus obtained into a salt, characterised by carrying out the reaction of (1R,2S,4R)-(xe2x88x92)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formula III and (2-{halogeno}-ethyl)-dimethylamine in a medium containing dioxane as a solvent. The invention is not limited to the use of dioxane as the sole solvent but also comprises the use of a solvent containing at least 50% by weight, preferably 75% by weight, of dioxane.
The essential feature of the process of the present invention is that the alkylation is carried out in a solvent which does not favour the alkylation reaction in position 3 of (+)-camphor of Formula II in the presence of a basic salt forming agent. It has been found that dioxane can be used advantageously for this purpose.
Conveniently a phenyl magnesium halide is used as a metallo-organic compound in a Grignard type reaction. Further examples are phenylalkali compounds, such as phenyllithium.
Preferably phenyl magnesium bromide is used. Phenyl magnesium chloride can also be used.
Suitably the process according to the invention may be carried out as follows:
In the first step of the process of the present invention (+)-camphor of Formula II is subjected to Grignard reaction with, for example, phenyl magnesium bromide. The reaction is carried out in a manner known per se. As reaction medium preferably tetrahydrofurane may be used. Phenyl magnesium bromide may be used in an amount of 1 to 3 moles, preferably about 1.5 mole, related to 1 mole of (+)-camphor of Formula II. One may proceed preferably by preparing first the Grignard reagent from magnesium and bromo benzene in the solvent used and thereafter adding the solution of the (+)-camphor of Formula II in an organic solvent at the boiling point of the reaction mixture. It is preferred to use the same solvent for the preparation of the Grignard reagent and the dissolving of the (+)-camphor of Formula II. As a solvent advantageously tetrahydrofurane may be used. Advantageously the reaction is carried out at the boiling point of the reaction mixture.
The reaction mixture is then cooled and the adduct obtained is hydrolysed. Hydrolysis may be carried out in a known manner, preferably in acidic medium. It is preferred to use hydrochloric acid for this purpose.
The (1R,2S,4R)-(xe2x88x92)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formula III obtained after decomposition of the Grignard complex can be subjected to alkylation without purifying the reaction mixture containing the same. The reaction can be carried out in the presence of unreacted (+)-camphor of Formula II. However, this leads to the formation only of a minor amount of alkylated by-products because according to the process of the present invention the formation of (1R,3S,4R)-3-[(2xe2x80x2-N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one of Formula V is suppressed.
As already mentioned above, alkylation is carried out in a solvent which does not favour the alkylation reaction in position 3 of (+)-camphor of Formula II, i.e. in which (+)-camphor of Formula II is alkylated in position 3 at most only to a very small extent. Dioxane is used as organic solvent because in a medium containing dioxane the alkylation of (+)-camphor of Formula II takes place at most only to a very small extent and consequently the amount of the undesired (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one of Formula V in the end product (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I is not more than 0.2% by weight.
The asymmetrical centers of (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I in positions 1 and 4 are derived from the (+)-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one {(+)-camphor} of Formula II.
The alkylation is carried out in the presence of a basic salt forming agent. The term xe2x80x9cbasic salt forming agentxe2x80x9d means basic compounds which convert the hydroxy group into a salt. For this purpose advantageously alkali metal amides, e.g. sodium amide, or alkali metal hydrides, e.g. sodium hydride, may be used. It is preferred to use sodium amide.
Preferably as a (2-{halogeno}-ethyl)-dimethylamine (2-{chloro}ethyl)-dimethylamine is used.
Suitably the basic salt forming agent is used in an amount of 1 to 3 moles, preferably 1.5 to 2 moles, related to 1 mole of the (1R,2S,4R)-(xe2x88x92)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formula II. The amount of the alkylating agent is advantageously 1.0 to 2.5 moles, preferably 1 to 1.1 mole, related to the basic salt forming agent. Preferably the alkylation reaction of (1R,2S,4R)-(xe2x88x92)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol of Formula III with the (2-{halogeno}-ethyl)-dimethylamine is carried out under heating, particularly at the boiling point of the reaction mixture. Suitably the reaction takes place within about 3 to 5 hours. An advantageous reaction time is about 4 hours.
The (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I may be converted into a pharmaceutically acceptable salt, preferably the fumarate, optionally without isolation of the former. One may preferably proceed as follows: from the reaction mixture obtained after alkylation the inorganic salts are removed by filtration at 0 to 30xc2x0 C., preferably at 20xc2x0 C., whereupon the corresponding pharmaceutically acceptable acid, preferably fumaric acid, is added to the filtrate in an approximately equimolar amount (1.0 to 1.5 mole). The crystalline product precipitated from the medium, such as the dioxane medium, is filtered off.
Since the (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I or pharmaceutically acceptable acid addition salts thereof, particularly the (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane fumarate (1:1) obtained by the process according to the invention contain[s] in accordance with the requirements of Pharmacopoeia not more than 0.2% of (1R,3S,4R)-3-[(2xe2x80x2-{N,N-dimethylamino}-ethyl)]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-one of Formula V or of the pharmaceutically acceptable acid addition salt thereof, respectively, by the process according to the invention recrystallization from dimethyl formamide anyhow leading only to insufficient purification used by known methods has been eliminated, and thus there is no need to remove traces of dimethyl formamide from the pharmaceutically active principle by methods unsuitable for the given purpose, too. Also this latter is a significant progress in view of the impossibility to remove dimethyl formamide to the necessary extent because of its high boiling temperature at which (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane of Formula I would be decomposed.
The invention also includes compounds of the Formula I, and pharmaceutically acceptable acid addition salts thereof, characterized in that they contain not more than 0.2% of the compound of Formula V or of a pharmaceutically acceptable acid addition salt thereof, and also characterized in that they are essentially free of dimethyl formamide. According to an embodiment of the invention, the compounds are completely free of dimethyl formamide. By being xe2x80x9cessentially freexe2x80x9d of dimethyl formamide, the presence of any minimal amount of dimethyl formamide, if it is present at all, does not limit or preclude the use of the compounds for administration to a host. Compounds that meet Pharmacopoeia limits or U.S. Federal Food and Drug Administration limits on the amount of dimethyl formamide in a compound to be administered to a host are also xe2x80x9cessentially freexe2x80x9d of dimethyl formamide. Compounds having 0.088% of dimethyl formamide or less by weight, or 880 ppm or less of dimethyl formamide, are also xe2x80x9cessentiallyxe2x80x9d free of dimethyl formamide.
The advantage of the process of the present invention is that in addition to providing a highly pure product meeting the strict requirements of Pharmacopoeia it can be carried but with excellent yields. Thus the yield of about 46% shown in the Examples is considerably higher than the yields disclosed in the Prior Art which do not surpass 25% even if (+)-camphor is re-circulated several times.
A further subject matter of the invention are medicaments characterised by that they contain as [an] principle(s) 1 or more compound(s) according to the invention within the above definition, advantageously together with 1 or more in pharmaceutical preparations usual excipient(s).
Preferably the medicaments according to the invention contain (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane fumarate (1:1) according to the invention within the above definition as an active principle.
Suitably the medicaments according to the invention are in the form of pharmaceutical preparations. They may be prepared by known methods of the pharmaceutical technique. The preparations are preferably suitable for oral administration, e.g. tablets, coated tablets, capsules, solutions, emulsions or suspensions, or for parenteral administration, e.g. intravenous, percutaneous or intramuscular injectable solutions. The compositions may contain usual carriers, e.g. starch, lactose and/or calcium carbonate, and/or water, polyalkylene glycols, sodium chloride solution and/or dextrose solution. The pharmaceutical preparations may also contain usual pharmaceutical auxiliary agents, e.g. emulsifying, stabilising, suspending and/or disintegrating agents, salts to modify the osmotic pressure, buffers and/or antioxidants.
A still further subject matter of the invention is the use of the compounds according to the invention within the above definition for preparing anxiolytic medicaments.
Preferably (1R,2S,4R)-(xe2x88x92)-2-[(2xe2x80x2-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane fumarate (1:1) is used as a compound according to the invention within the above definition.